Discovery of SY-589, a Highly Potent and Orally Bioavailable Polθ Helicase Inhibitor for the Treatment of HR-Deficient Tumors

  • J Med Chem. 2026 Feb 12;69(3):2789-2813. doi: 10.1021/acs.jmedchem.5c02689.
Chongxun Ge  1  2 ,  Dazhi Feng  1 ,  Song Shi  2 ,  Xuzhen Tang  2 ,  Yaqi Cui  2 ,  Song Liu  2 ,  Yunyue Wang  1 ,  Shuangtian Tang  1 ,  Xinnan Li  1 ,  Xianqiang Sun  3 ,  Daopeng Yuan  4 ,  Jinyi Xu  1 ,  Hu He  2 ,  Hong Yao  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China.
  • 2. Hangzhou SynRx Therapeutics Biomedical Technology Co., Ltd., 1390 Cangxing Road, Hangzhou 311121, P. R. China.
  • 3. AutoDrug Biotech Co., Ltd., 298 XiangKe Road, Zhangjiang Hi-Tech Park, Shanghai 201210, P. R. China.
  • 4. School of Medicine, Tsinghua University, Beijing 100084, P. R. China.
PMID: 41575169 DOI: 10.1021/acs.jmedchem.5c02689
Abstract

DNA Polymerase theta (Polθ), which mediates microhomology-mediated end joining (MMEJ) in homologous recombination-deficient (HRD) cancers, has recently emerged as a compelling synthetic lethal target. Combining Polθ inhibition with PARP inhibitors represents a promising strategy to overcome PARP Inhibitor resistance. Here, we present the discovery of SY-589, a highly potent (ATPase IC50 = 2.29 nM), selective (selectivity index >1800), and orally bioavailable (F = 107%) Polθ helicase inhibitor, which exhibits robust antitumor efficacy in HRD tumors in vitro (CTG IC50 = 2.71 nM). Notably, SY-589 synergized strongly with the PARP Inhibitor Olaparib in vitro (Loewe score >20) and in vivo (TGI = 109%), enhancing antitumor effects while permitting reduced Olaparib dosing. Overall, SY-589 is a promising candidate of Polθ inhibitor and has been positioned as a rational combination partner with PARP inhibitors, aiming to overcome PARP Inhibitor resistance and mitigate their dose-limiting toxicities.

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